Symptomatic Advanced CLL

Overview

Chronic lymphocytic leukemia (CLL) is a heterogenous disease with some patients progressing rapidly and others living for years without treatment. Nevertheless, most patients with symptomatic advanced CLL receive treatment. Accepted indications for the initiation of treatment of CLL include the following:

• Anemia (hemoglobin level less than 11.0 g/dL)
• Thrombocytopenia (platelet count less than 100,000/mm³)
• Massive or progressive enlargement of lymph nodes
• A lymphocyte doubling time of less than six months
• Fever, weight loss, night sweats or profound fatigue

A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the treatment of advanced-stage symptomatic CLL. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

There have been tremendous advances in the treatment of CLL over the past decade and especially over the past five years. CLL was once described as a chronic disease with treatment being exclusively palliative, with the exception of allogeneic stem cell transplantation which can cure some patients but is associated with a high treatment-related mortality. Now, complete molecular remissions and long-term disease-free survival can be achieved with one of several combination chemotherapy and antibody regimens. With a curative potential possible it becomes more important to determine when patients should be treated and how aggressively. A comprehensive approach to treating patients with CLL now involves risk stratification for newly diagnosed patients; adherence to supportive care guidelines; attention to quality of care issues specific to patients with CLL; and consideration of age, other health conditions, and quality of life.

A wide range of effective treatment regimens is available for the initial treatment of CLL, which can make it confusing to plan treatment. Many treatment options have been shown to prolong survival and improve quality of life. Each treatment is associated with side effects or toxicity from treatment. When a treatment is not curative, it may be more appropriate to select the therapy with the least toxicity.

Recent studies have suggested that patients with CLL who achieve a complete remission will have a longer survival than patients who do not achieve a complete remission. Furthermore, a complete molecular remission is associated with the best survival. Complete remission is usually defined as absence of abnormal lymphocytes in blood and bone marrow, no enlarged lymph nodes, and normal blood counts. A complete molecular remission is determined by performing polymerase chain reaction (PCR) tests on blood and bone marrow which can detect CLL that cannot be seen under the microscope. More recently, researchers have suggested that younger and more fit patients with CLL should be treated aggressively with the goal of producing a complete molecular remission. However, many elderly patients and those with significant other diseases (comorbidities) are usually treated with a less aggressive single agent approach in order to decrease side effects.

Currently available standard treatment includes the following:

Single Agent Chemotherapy

Many patients with CLL are treated with single agents due to age and other health problems. Single agent therapy is given to relieve symptoms and improve quality of life because toxicities are generally less severe than with combination therapy. Some of the most often-used agents are Leukeran^® (chlorambucil) and Fludara^® (fludarabine) and, more recently, Rituxan^® (rituximab), Campath^® (alemtuzumab), and Treanda^® (bendamustine). However, Rituxan is more commonly used in combination therapy than as single agent therapy.

Leukeran^® (chlorambucil): an oral alkylating agent, was the primary initial treatment of for CLL for 40 years, before the development of newer agents such as Fludara and Rituxan. This drug has, in general, been replaced with newer agents called purine antagonists, such as Fludara, for initial treatment of CLL. However, a recent study has suggested that while initial treatment with Fludara and Fludara combinations has improved response rates and time to disease progression, this may not be associated with an improved overall survival.1 Thus, the sequence of treatment of patients with CLL may be important since most available drugs will be used a some point in management of the disease.

A recent randomized trial suggested that chlorambucil was better than Fludara for the initial treatment of patients older than 64 years of age.2 This study was carried out between 1999 and 2004 and involved 206 CLL patients over the age of 64. Eighty-five percent of patients in this study were Binet stage B-C. The median age was 70 years. Patients were randomly allocated to receive Fludara on days 1-5 every 28 days for six courses or chlorambucil every 15 days for up to 12 months with an allowance for dose escalation. Table 1 summarizes the main findings of this trial.

Table 1: Chlorambucil versus Fludara for initial treatment of elderly CLL.

	Chlorambucil	Fludara
Number of Patients	105	101
Average Treatment Duration	6.5 months	4.9 courses
Complete Remission	0%	7%
Overall Response	59%	86%
Progression-Free Survival	17.8 months	18.7 months
Deaths	34%	46%
Overall Survival	63.6 months	45.9 months
Rescue Treatment	62%	39%

 
These data suggest that older patients may not benefit from up-front therapy with Fludara or possibly Fludara-based regimens. The main problem appears to be a poor response to salvage therapy after initial failure.

Fludara^® (fludarabine): Fludara is a type of chemotherapy and is the first of a new class of drugs (purine analogs) active in the treatment of CLL. Researchers in Germany treated 81 previously untreated patients with Fludara alone.3 They reported an overall response rate of 72% with complete remissions in 37%. The average time to disease progression was 841 days.

Campath^® (alemtuzumab): Campath is a fully human monoclonal antibody that selectively targets the CD52 antigen, which is expressed more prominently on malignant lymphocytes than other cells. The binding of Campath stimulates destruction of the malignant lymphocytes and reduction or elimination of cancerous cells throughout the bone marrow, blood and lymph system.

An international phase III trial demonstrated that Campath provides significantly superior responses with a favorable toxicity profile when compared with chlorambucil as initial therapy of CLL.4 This trial included 297 previously untreated patients with progressive B-cell CLL who were randomly allocated to receive Campath or chlorambucil. Campath provided significantly better responses, even among poor-prognosis patients, than chlorambucil. Furthermore, the toxicity profile of patients treated with Campath remained favorable.

• Overall response rates were 27% higher for patients treated with Campath than for patients treated with chlorambucil.
• Responses were also higher in patients with adverse cytogenetics (11q deletions and 17p deletions)

Researchers stated that side effects were acceptable with Campath. Further studies also confirmed that specific “bad” cytogenetics in CLL were associated with superior responses to Campath compared to chlorambucil.5

Treanda^® (bendamustine): Treanda is a chemotherapy drug that has both alkylator and purine-like activity. One advantage of Treanda is that it is not cross-resistant with other alkylating agents such as chlorambucil. Treanda has been marketed and used clinically in Germany for many years in patients with non-Hodgkin’s lymphoma (NHL), CLL, multiple myeloma, breast cancer and other solid tumors such as lung cancer.

The study that led to FDA approval of Treanda was a multicenter trial that included 301 patients with previously untreated CLL.6 Symptomatic patients requiring treatment received initial therapy with either Treanda or chlorambucil, an alkylating agent that is FDA approved for the treatment of CLL as well as several types of lymphoma.

• Overall response rates among patients treated with Treanda were 59% compared with 26% among the chlorambucil-treatment group.
• Additionally, complete response rates were seen in 8% of the patients treated with Treanda compared with less than 1% of those treated with chlorambucil.
• The average progression-free survival period for the Treanda treatment group was 18 months, 12 months longer than for those treated with chlorambucil.
• 79% of patients treated with chlorambucil experienced side effects compared with 89% of patients treated with Treanda. Side effects included the need for red blood cell transfusions and were more likely among patients treated with Treanda (20%) compared with those treated with chlorambucil (6%).

Researchers concluded that Treanda should replace chlorambucil for the treatment of CLL, as has been done in some European countries. Future research may investigate the use of Treanda within the United States for treatment of non-Hodgkin’s Lymphoma, multiple myeloma, breast cancer, and other solid tumors such as lung cancer.

Combination Therapies

Combination regimens are increasingly being used in younger, more healthy patients with CLL. The strategy that is commonly used is to attempt to produce a complete remission with induction therapy, to administer consolidation therapy after complete or partial remission to produce a molecular remission, and then to administer maintenance therapy to prevent recurrences.

Rituxan^® (rituximab) is the main drug that has been added to chemotherapy in the past decade to treat patients with CLL and is utilized in most up-front treatment regimens. Fludara is a common component of most combination regimens. Campath is increasingly being added to chemotherapy combinations and to some regimens that include Rituxan. Cytoxan^® (cyclophosphamide), an alkylating agent, and mitoxantrone (Novantrone^®), an anthracycline, are rarely used as single agents but are often used in combination regimens.

Fludara plus Cytoxan (FC): A randomized trial has shown that the addition of Cytoxan to Fludara improves the overall and complete response rates of previously untreated patients with CLL.7 The overall response rate was 74% for combination therapy and 60% for Fludara alone. Combination therapy also increased progression-free survival from 19 to 32 months. There did not appear to be an increase in infectious complications or a decrease in quality of life measurements.

Fludara, Cytoxan, and Rituxan (FCR): Previous studies from the MD Anderson Cancer Center showed that a regimen of Fludara, Cytoxan, and Rituxan (FCR) produced results superior to any previously tested regimens for treatment of refractory or newly diagnosed CLL.89 The study in 224 previously untreated patients with CLL showed a complete remission rate of 70%, a partial remission rate was 25% for an overall response rate of 95%. Flow cytometry studies showed that two-thirds of the patients had less than 1% CD5- and CD19-positive cells in the bone marrow. At two years, over 90% of patients were alive and over 80% had not progressed; all complete responders were alive. Infectious episodes occurred in a third of all patients. These results were significantly better than previous results observed with other regimens at M. D. Anderson Cancer Center.

Due to concern over neutropenia (low white blood cell count) and infectious complications with standard doses of FCR, there have been attempts at dose reduction of this regimen. Recently, researchers from the University of Pittsburgh presented data on FCR-Lite.10 In this study the doses of Fludara and Cytoxan were reduced and the doses of Rituxan increased for the treatment of 50 patients with previously untreated CLL. Grade 3-4 neutropenia occurred in 12% of patients and only 2 episodes of neutropenic fever occurred. Grade 3-4 thrombocytopenia occurred in 7% and anemia in 2.5%. The complete response rate was 85% and the partial response rate was 15%. These authors suggested that this was a tolerable and very effective regimen for newly diagnosed patients with symptomatic CLL.

Researchers from Austria reported results of a regimen that gave FCR for three cycles followed by three cycles of FR in 43 previously untreated patients with CLL.11 The complete response rate after three cycles was 83% which increased to 94% after three cycles of FR. After six cycles of therapy 59% were negative for minimal residual disease (MRD). 13% had grade 4 hematological toxicities and 13% had grade 3 infections. There were no treatment-related deaths.

These latter two studies suggest that fine tuning of the FCR regimen can maintain effectiveness and may decrease some of the toxicities. Both of the studies of reduced dosage of FCR included patients in their early 80’s.

Fludara, Cytoxan and Mitoxantrone (FCM) with or without Rituxan: The combination of Fludara, Cytoxan and mitoxantrone (FCM) was a common regimen for CLL prior to the use of Rituxan. Subsequent studies have shown that adding Rituxan to this regimen improves outcomes of patients with CLL. Recently, researchers from the UK presented the results of a randomized phase II study comparing FCM with and without Rituxan in patients with previously treated CLL.12 Table 2 summarizes the main findings of this trial:

Table 2: Fludara, Cytoxan and Novantrone with or without Rituxan for treatment of CLL

	FCM	FCMR
Number of Patients	23	23
Overall Response	57%	70%
Complete Response	13%	43%
Early Death	9%	9%
MRD Negative	9%	22%

 
Although the numbers are small, these data support the addition of Rituxan to this and probably other chemotherapy regimens; this has become a standard approach for treating newly diagnosed patients with CLL.

Cytoxan, Fludara and Campath (FCC): Researchers affiliated with CALGB Study 10101 reported that consolidation therapy with Campath resulted in severe toxicity in previously untreated patients who achieved a complete response after Cytoxan and Fludara therapy.13 These researchers reported a high rate of infectious complications in patients in complete response receiving Campath consolidation although they continue to evaluate this approach in patients not achieving a complete response.  Infectious complications occurred both during and after the administration of Campath.

Cytoxan, Fludara, Campath and Rituxan (CFAR): Researchers from the M. D. Anderson Cancer Center have reported that CFAR shows promising results for the treatment of high-risk CLL.14 The CFAR regimen was evaluated in 40 patients with newly diagnosed CLL. All patients were 69 years of age or younger with a median age of 63 years. All patients received Neulasta^® (pegfilgrastim) and prophylaxis against cytomegalovirus and pneumocystis carinii pneumonia. The researchers reported that adding Campath to the FCR regimen did not increase toxicity compared to previous experience with the FCR regimen. The complete remission rate was 69% and the partial response rate was 27%. Five patients were classified as partial responders due to persistent low blood cell counts. They also reported that 83% of patients with a complete hematological response had complete molecular remissions. It would appear that high-risk patients with CLL benefit from the CFAR regimen.

Nipent, Cytoxan and Rituxan (PCR): Researchers from Ohio State University and the Mayo Clinic have reported that the treatment combination consisting of Nipent^® (pentostatin), Cytoxan and Rituxan (PCR) demonstrates high activity in previously untreated patients with CLL with high-risk factors.15 This study evaluated PCR in 64 patients with previously untreated high-risk CLL. The median age was 63 years, with the oldest patient being 80 years old. The treatment regimen consisted of 21 day cycles of PCR for a projected six cycles with prophylaxis against cytomegalovirus and Pneumocystis carinii. The median follow-up of this study was 26 months. These authors reported an overall response rate of 91% with a median duration of response of 34 months. The complete response rate was 41% and the partial response rate was 50%. Progression-free survival was 32.6 months. Eighty-six per cent of patients are alive at the time of this report, and 38% have progressive disease.

The death rate during treatment was 3.2%. Forty percent of patients had grade 3-4 neutropenia and 20% had grade 3-4 thrombocytopenia. Six patients had upper respiratory infections and one had fever without neutropenia. Life-threatening infections did not appear to be a major problem.

These results appear to be comparable to Fludara-based regimens with possibly fewer infectious complications. Only a direct comparison can determine relative effectiveness and determine if there are fewer infections with Nipent-based versus Fludara-based regimens.

Rituxan and Campath: A study from the M. D. Anderson Cancer Center has shown that the co-administration of Rituxan and Campath results in significant responses in patients with refractory CLL. Toxicities associated with these two agents were not excessive. A recent small study evaluated Rituxan and Campath in 10 patients with previously untreated poor-risk CLL.16 Patients were treated with Campath three times a week and Rituxan was given every two weeks for eight doses. All patients received antibiotic prophylaxis and were monitored for the development of cytomegalovirus infection. The median age for these patients was 52 years, the median white blood cell count was 48,000 and the follow-up was 10 months. All ten patients achieved a complete response in the peripheral blood and bone marrow. Seven of the 10 patients achieved a clinical complete response in lymph nodes. The main side effects were lymphopenia in all patients and neutropenia in six patients. Four patients developed cytomegalovirus infection and were treated with ganciclovir. This appears to be a very active antibody combination for the treatment of CLL. Infectious side effects appear to be manageable.

Supportive Care

Infections remain a major cause of morbidity and mortality in patients with CLL. These infections are related to immune defects inherent to CLL as well as to therapy-related immunosuppression. Infectious complications are increased with the use of Fludara and monoclonal antibodies such as Rituxan and Campath compared to treatment with chemotherapy alone. Although bacterial infections are the most common; fungal and herpesvirus infections are also seen with use of these agents. Infections such as Pneumocystis carinii and cytomegalovirus pneumonias are due to reactivation of these organisms already present in the body.

Several steps can be taken to  improve the survival and well being of patients with CLL:

Intravenous Immunoglobulin: Intravenous immunoglobulin should be administered to patients with low levels of gamma globulin for infection prevention.17

Pneumocystis carinii: Pneumocystis carinii (now called jiroveci) is a common lung infection in immunosuppressed patients caused by a fungus. Pneumonia due to this infection can be prevented by the prophylactic administration of cotrimoxazole or another appropriate drug.

Cytomegalovirus: Cytomegalovirus causes pneumonia in immunosuppressed patients and can be prevented by the prophylactic administration of valganciclovir or another appropriate drug.18

Bacterial Infections: The prophylactic administration of a systemic broad-spectrum antibiotic is indicated for CLL patients receiving combination therapy. Patients should also be vaccinated with pneumococcal vaccine.19

Fungal Infections: Antifungal agents are used to prevent or treat fungal infections which are common in CLL.

Neutropenia: Neulasta^® (pegfilgrastim) or Neupogen^® (filgrastim) are frequently administered prophylactically to patients receiving combination chemotherapy and antibody therapy for CLL to hasten recovery of granulocytes in the blood.

Anemia: Anemia due to chemotherapy can be prevented or treated with Aranesp^® (darbepoetin alfa) or Epogen^® (epoetin alfa).

Strategies to Improve Treatment of CLL

The progress that has been made in the treatment of advanced-stage CLL has resulted from the incorporation of new anti-cancer agents into treatment regimens and the performance of clinical trials. Future progress will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving treatment.

Leustat^® (cladribine): An international randomized study has shown that Leustat (cladribine, CdA) may be superior to Fludara or chlorambucil for the initial treatment of patients with chronic lymphocytic leukemia (CLL).20 Leustat is used primarily to treat hairy cell leukemia, but has also been evaluated as a single agent for the treatment of mantle cell lymphoma (MCL) with significant activity. A recent study evaluated Leustat and Rituxan for the initial treatment of CLL.21 Patients received Neupogen^® (filgrastim) or Neulasta^® (pegfilgrastim) due to significant neutropenia in the first patients treated. The median age of the patients in this study was 70 years with the oldest being 86 years old. The complete response rate was 52% with only one of these patients relapsing. Four patients achieved a partial response. Most patients received further therapy after failure to respond or progression, but 90% were alive at the time of this report. These authors concluded that Leustat and Rituxan were well tolerated and produced durable remissions in half the patients treated.

Another study involved 229 previously untreated symptomatic patients with CLL who were randomly allocated to receive treatment with Leustat, Fludara or high-dose intermittent chlorambucil. The results of this trial are shown in table 4.

Table 4: Leustat vs Fludara vs chlorambucil for newly diagnosed CLL.

	Leustat	Fludara	Chlorambucil
Number of Patients	72	73	76
Overall Response Rate	75%	70%	62%
Median Time to Progression	25 months	10 months	9 months
Median Time to Second Line Treatment	50 months	24 months	21 months

 
There were more infections in patients receiving Fludara or Leustat than in patients receiving chlorambucil. Survival was equivalent in all three groups, reflecting the efficacy of second-line therapy. These authors concluded that Leustat prolonged time to disease progression and time to second-line therapy for symptomatic CLL patients. These are interesting results and could mean more trials of Leustat in B-cell diseases where Fludara has been the drug of choice for over a decade.

Genasense^® (oblimersen): Genasense is being evaluated for the treatment of multiple myeloma, acute myeloid leukemia, CLL, melanoma, and acute lymphoid leukemia. Genasense down-regulates a protein known as Bcl-2. Bcl-2 is a potent inhibitor of apoptosis (programmed cell death). Over-expression of this protein in patients with a variety of malignancies is associated with resistance to chemotherapy. Genasense has been investigated in several hematologic malignancies where Bcl-2 has been implicated in disease resistance.

Researchers involved in a multicenter trial have reported that the addition of Genasense^® (oblimersen, Bcl-2 antisense) to Fludara and Cytoxan improves the survival of patients with relapsed or refractory CLL who achieve a complete remission (CR) or near complete remission (nCR).22

In a previous report on 241 patients with advanced CLL treated with Fludara and Cytoxan with or without Genasense, the addition of Genasense increased the proportion of patients who achieved CR/nCR from 7% in the Fludara/Cytoxan only arm to 17% in the Genasense arm. Responses were also more durable in the patients receiving Genasense. Overall response rates were not different between the two groups. Maximum benefit was observed in Fludara-sensitive patients, who had a four-fold increase in the complete or near-complete response rate. The estimated median survival was 33.8 months in the Genasense group and 32.9 months in the chemotherapy-only group. The estimated three-year survival rate was 46% for the Genasense group and 37.5% for the chemotherapy only group.

Based on these results and the results of a follow-up analysis, it was concluded that the addition of Genasense to Fludara and Cytoxan increased the complete response rate, complete response duration, and survival of patients achieving complete response. These results indicate that Genasense is active in patients with CLL. Further studies will be needed to determine if this agent should be tested for initial therapy of CLL.

References:

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